1. Field of the Invention
The present invention relates to the field of medical arts; more particularly to broad range inhibitors of nuclear factor kB (NF-kB) and the use of these inhibitors in cancer therapy and in treating inflammatory diseases.
2. Background
Nuclear Factor-kB (NF-kB)
NF-kB is a transcription factor controlling a variety of biological responses. It appears to be involved in several human diseases, including, among others, cancer, stroke, diabetes and AIDS. NF-kB is composed of a family of related proteins with a conserved central region, which is known as the Rel homology domain. This region is involved in DNA binding, interactions with IkB (inhibitor molecules) and dimerization. The five related-family members in mammals include p50/p105, p65/RelA, cRel, RelB and p52/p100. There are multiple dimeric forms of NF-kB which form homo and heterodimers, with some forms more dominant than others.
There are several forms of NF-kB inhibitor, IkB. IkBs inhibit NF-kB formation by retaining these dimers in the cytoplasm or preventing them from binding to the kB element, not by inhibiting formation of the dimeric form of NF-kB. Typical IkBs tend to bind specific NF-kB species. IkBα for example exhibits homology with the COOH terminus of the p105 of NF-kB, while IkBβ and IkBε interact with similar subunits. Each inhibitor tends to control specific kB species, so that none of the currently known IkB inhibitors prevents NF-kB interaction with all NF-kB species.
NF-kB is rapidly activated in the cell by stimuli such as inflammatory cytokines, including TNF-α, IL-1, T-cell activation signals, growth factors and stress inducers. Once activated, NF-kB binds to target DNA elements in the nucleus causing positive regulation of gene transcription involved in immune and inflammatory responses, cell growth and, importantly, apoptosis. Among the genes regulated by NF-kB are the interleukins such as IL-2, IL-6, IL-8, IL-2 receptor, IL-12 p40 subunit, VCAM-1, ICAM-1, TNF-α, IFN-γ and cMyc.
Apoptosis is of particular interest because once activated, NF-kB inhibits apoptosis. Under normal conditions, NF-kB activation is transient because of mechanism within the cell that cause its deactivation. Oncoproteins have been demonstrated to activate NF-kB, which by inhibiting apoptosis allow cell proliferation. Thus there is the desirability of preventing the action of NF-kB in treating malignancies, particularly when anti-cancer drugs intended to promote apoptosis are administered.
Additionally, NF-kB is thought to be a primary effector in a number of human diseases. The molecule is the subject of current research aimed at understanding its action and to apply this knowledge to the development of agents that can be used alone or in conjunction with anticancer and anti-inflammatory drugs.
Deficiencies in the Art
There is a recognized need to identify compositions that inhibit NF-kB activity, particularly due to its role in inflammation and apoptosis. Several NF-kB inhibitors have been prepared, but none is effective against all NF-kB species. There is therefore a need for a broader “super repressor” NF-kB inhibitor that interacts with p50 and p52 as well as RelB and would be an effective adjuvant in cancer and anti-flammatory therapy.